EP0049308B1 - Dérivés de chromone - Google Patents

Dérivés de chromone Download PDF

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Publication number
EP0049308B1
EP0049308B1 EP80108060A EP80108060A EP0049308B1 EP 0049308 B1 EP0049308 B1 EP 0049308B1 EP 80108060 A EP80108060 A EP 80108060A EP 80108060 A EP80108060 A EP 80108060A EP 0049308 B1 EP0049308 B1 EP 0049308B1
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EP
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Prior art keywords
compound
chromone
bis
added
washed
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German (de)
English (en)
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EP0049308A1 (fr
Inventor
Seiichiro Nomoto
Hironori Ikuta
Yoshimasa Machida
Shigeto Negi
Isao Sugiyama
Hiroshi Yamauchi
Kenro Nakatsuka
Isao Saito
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Eisai Co Ltd
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Eisai Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • This invention relates to new chromone derivatives having the formula (I): wherein A represents a hydrogen atom, a halogen atom or a hydroxyl group, and R 1 represents an alkyl group with 1-3 carbon atoms or a chloro-substituted alkyl group with 1-3 carbon atoms.
  • EP-A-03 115 describes essentially penicillin derivatives having a chromone ring as anti-bacterial compounds. No example is given for the preparation of cephalosporin compounds possessing a chromone ring.
  • US-A-4,159,268 also discloses penicillin derivatives having a chromone ring; however, no practical example for the synthesis thereof is given.
  • halogen atom in the formula (1) there are mentioned the chlorine atom and bromine atom.
  • alkyl group with 1-3 carbon atoms there are mentioned methyl, ethyl and propyl.
  • chloro-substituted alkyl group with 1-3 carbon atoms there is mentioned 2,2,2-trichloroethyl group for example.
  • the compound of this invention is useful as an intermediate for synthesis of the above compound (II). More particularly, the above compound (II) can be synthesized by the use of the compound of this invention as shown in the following scheme:
  • the compound of the formula (II) can be produced by means of a one-pot reaction through the acid bromide as an intermediate, starting from the aldehyde of the formula (I-A) as mentioned above.
  • the compound of the formula (II) can be synthesized by reacting the carboxylic acid of the formula (I-B) with the compound of the formula (III), in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, N,N'-diethylcarbodiimide, N-cyclohexyi-,N'-morphorinoethylcarbodiimide, polyphosphoric acid ethyl ester, tosyl chloride, ethylchloroformate, phosphorus oxychloride and oxalyl chloride.
  • a condensing agent such as N,N'-dicyclohexylcarbodiimide, N,N'-diethylcarbodiimide, N-cyclohexyi-,N'-morphorinoethylcarbodiimide, polyphosphoric acid ethyl ester, tosyl chloride, ethy
  • the compound (I) of this invention can be prepared by means of the following procedures.
  • reaction of the compound of the formula (IV) with the compound of the formula (V) in step (1) can be carried out in the presence of a base such as pyridine, triethylamine or N-methylmorpholine at a temperature of preferably below room temperature.
  • a base such as pyridine, triethylamine or N-methylmorpholine
  • the reaction of the compound of the formula (VI) with dimethyl formamide in step (2) can be carried out by using an inert solvent such as benzene, toluene, ethyl ether tetrahydrofuran or dioxane or an excessive amount of dimethyl formamide, the reactant, instead of the solvent.
  • an inert solvent such as benzene, toluene, ethyl ether tetrahydrofuran or dioxane or an excessive amount of dimethyl formamide
  • the acid halide are phosphorus oxychloride, thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus pentachloride, benzoyl chloride and p-toluenesulfonyl chloride.
  • Oxidation of the compound of the formula (I-A) in step (3) is carried out using a chlorite-chlorine scavenger, a Jones reagent (chromic anhydride-sulfuric acid), sodium bichromate-sulfuric acid, etc. as an oxidizing agent.
  • a chlorite-chlorine scavenger a Jones reagent (chromic anhydride-sulfuric acid), sodium bichromate-sulfuric acid, etc.
  • the chlorite-chlorine scavenger system is most preferred in view of the yield of the product.
  • Sodium chlorite and potassium chlorite may be cited as examples of the chlorite.
  • the chlorine scavenger denotes a compound having the action of scavenging chlorine generated in the reaction system, and examples are sulfamic acid, resorcinol and pyroglutamic acid. Sulfamic acid is most preferred.
  • the oxidation reaction is carried out usually at -10 to 40°C, preferably 10 to 20°C.
  • reaction solvent examples include non-hydrophilic solvents such as dichloromethane, chloroform, dichloroethane, ethyl acetate, benzene and toluene. and hydrophilic solvents such as acetone, dioxane, tetrahydrofuran and acetonitrile.
  • An ordinary halogenating agent may be used as the halogenating agent for the preparation of the compound of formula (I-C) in step (4).
  • an acid chloride phosphorus pentachloride and thionyl chloride may be cited.
  • 2,4,5-Trihydroxyacetophenone (3.36 g) was dissolved in 150 ml of ethyl acetate, and 3.24 ml of pyridine was added at about -5°C with stirring. Then, 50 ml of a solution of 3.8 ml of ethyl chloroformate in ethyl acetate was added dropwise over 30 minutes. The mixture was stirred for 10 minutes at the same temperature. The resulting precipitate was collected by filtration and washed three times with 10 ml of ethyl acetate. The washings and the filtrate were combined, and the mixture was washed with water (once) and a saturated aqueous solution of sodium chloride (three times) and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl ether-ethanol. The crystals were collected by filtration, and washed with ethanol and n-hexane and dried to afford 4.60 g of the desired product.
  • the above compound a (37.47 g) was dissolved in 300 ml of dimethyl formamide. The solution was cooled to about -5°C, and with stirring, 120 ml of phosphorus oxychloride was added dropwise over 40 minutes. The mixture was stirred at room temperature for 5.5 hours. The reaction mixture was added to 3 liters of ice water, and stirred for 20 minutes. The resulting precipitate was collected by filtration, washed with water, and dissolved in ethyl acetate. The ethyl acetate solution was washed with water three times and dried over magnesium sulfate. The solvent was distilled off, and ethanol was added to the residue to solidify it. The solidified product was collected by filtration, washed with ethanol and n-hexane, and then dried to afford 28.5 g of the desired product.
  • the compound (1.05 g) obtained in b) of Example 1 was dissolved in 31.5 ml of dichloromethane; and a solution of 1.05 g of sulfamic acid in 18.9 ml of water was added at 10°C with stirring. Then, a solution of 525.6 mg of sodium chlorite in 1.2 ml of water was added. The solution was stirred at the same temperature for 1 hour, and allowed to separate.
  • the dichloromethane layer was washed with water (once) and then with a saturated aqueous solution of sodium chloride (twice), and dried over magnesium sulfate. The solvent was distilled off, and ethyl ether was added to the residue to solidify it. The solidified product was collected by filtration, and dried to afford 950 mg of the desired product.
  • Example 2 The compound (1.1 g) of Example 2 was dissolved in 20 ml of benzene, and 2 ml of thionyl chloride was added dropwise at room temperature with stirring. Then, the mixture was refluxed with stirring. The reaction mixture was concentrated, and n-hexane was added to the concentrate to crystallize it. The resulting crystals were collected by filtration, washed with n-hexane and dried to afford 980 mg of the desired product.
  • 2,4,5-Trihydroxyacetophenone (16.8 g) was dissolved in 500 ml of ethyl acetate, and 15.98 ml of pyridine was added at about -5°C with stirring. Then, a solution of 26.82 ml of 2,2,2-trichloroethyl chloroformate in 70 ml of ethyl acetate was added dropwise over the course of 2.5 hours. The mixture was stirred at the same temperature for 15 minutes. The precipitate formed was collected by filtration and washed with ethyl acetate.
  • the compound (25.95 g) obtained in a) above was dissolved in 125 ml of dimethyl formamide.
  • the solution was cooled to about -5°C, and with stirring, 50 ml of phosphorus oxychloride was added dropwise over 1 hour.
  • the mixture was stirred at room temperature for 5.5 hours.
  • the reaction mixture was added to 1.5 liters of ice water, and stirred for 20 minutes.
  • the precipitate formed was collected by filtration, and washed with water.
  • the product was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate.
  • the solvent was distilled off, and ethanol was added to the residue to solidify it.
  • the solidified product was collected by filtration, washed with ethanol and then with n-hexane, and dried to afford 18.5 g of the desired product.
  • Example 4 The compound (838.4 mg) obtained in Example 4, b) was dissolved in 16 ml of dichloromethane, and with stirring at 10°C, a solution of 525 mg of sulfamic acid in 9.5 ml of water was added, followed by addition of a solution of 262.8 mg of sodium chlorite in 0.6 ml of water. The mixture was stirred for 1 hour at the same temperature. The reaction mixture was allowed to separate. The dichloromethane layer was washed with water and then with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl ether to afford 685 mg of the desired product.
  • Example 5 The compound (57.3 mg) obtained in Example 5 was dissolved in 10 ml of benzene, and with stirring at room temperature, 0.5 ml of thionyl chloride was added. The mixture was refluxed for 3 hours with stirring. The reaction mixture was concentrated, and 5 ml of n-hexane was added to the concentrate to crystallize it. The resulting crystals were collected by filtration, washed with n-hexane and dried to afford 34.8 mg of the desired product.
  • the mixture was stirred at 0°C for 1 hour.
  • the reaction mixture was concentrated to about 5 ml.
  • the concentrate was added to 75 ml of 0.25 N hydrochloric acid cooled with ice.
  • the precipitate formed was collected by filtration, washed with water and dried to afford 0.431 g of the desired product.
  • Cephaloglycine (0.405 g) was suspended in 10 ml of ethyl acetate, and to the suspension was added 0.50 ml of N,O-bis(trimethylsilyl)acetamide at 0°C with stirring. The mixture was stirred at room temperature for 1 hour. A suspension of 0.385 g of the acid chloride of Example 3 in ethyl acetate was added to the resulting solution at 0°C with stirring, and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off, and the residue was dissolved in 5 ml of acetone. The solution was added dropwise to 70 ml of 0.25N hydrochloric acid at 0°C with stirring. The resulting precipitate was collected by filtration, washed with water, and then dried to afford 0.654 g of a crude product. The crude product was washed with ethyl ether, and dried to afford 0.600 g of the desired product.
  • the reaction mixture was concentrated to 5 ml, and the concentrate was added dropwise to 20 ml of 0.5N hydrochloric acid with stirring.
  • the resulting precipitate was collected by filtration, washed with water, and then dissolved in ethyl acetate.
  • the solution was washed with water three times, and dried over magnesium sulfate.
  • the solvent was distilled off, and the residue was dissolved in 5 ml of ethyl acetate.
  • the solution was added dropwise to 50 ml of ethyl ether with stirring.
  • the resulting precipitate was collected by filtration, washed with ethyl ether and dried to afford 550 mg of the desired product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (4)

1. Dérivés de chromone répondant à la formule:
Figure imgb0033
dans laquelle A représente un atome d'hydrogène, un atome d'halogène ou un radical hydroxyle, et R1 représente un radical alkyle ayant 1 à 3 atomes de carbone ou un radical chloro-alkyle ayant 1 à 3 atomes de carbone.
2. Composé selon la revendication 1, où le dérivé de chromone est le 6,7- bis(éthoxycarbonyloxy)chromone-3-carboxaldéhyde.
3. Composé selon la revendication 1, où le dérivé de chromone est l'acide 6,7- bis(éthoxycarbonyloxy)chromone-3-carboxylique.
4. Composé selon la revendication 1, où le dérivé de chromone est le chlorure de 6,7- bis(éthoxycarbonyloxy)chromone-3-carbonyle.
EP80108060A 1980-10-07 1980-12-19 Dérivés de chromone Expired EP0049308B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP55139269A JPS5764698A (en) 1980-10-07 1980-10-07 Cephem derivative, its preparation, and antibacterial agent composed of said derivative
JP139269/80 1980-10-07

Publications (2)

Publication Number Publication Date
EP0049308A1 EP0049308A1 (fr) 1982-04-14
EP0049308B1 true EP0049308B1 (fr) 1985-07-03

Family

ID=15241343

Family Applications (2)

Application Number Title Priority Date Filing Date
EP80108060A Expired EP0049308B1 (fr) 1980-10-07 1980-12-19 Dérivés de chromone
EP80108062A Expired EP0049309B1 (fr) 1980-10-07 1980-12-19 Dérivés de céphalosporine, leur préparation et compositions pharmaceutiques les contenant

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP80108062A Expired EP0049309B1 (fr) 1980-10-07 1980-12-19 Dérivés de céphalosporine, leur préparation et compositions pharmaceutiques les contenant

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US (2) US4352801A (fr)
EP (2) EP0049308B1 (fr)
JP (1) JPS5764698A (fr)
DE (2) DE3070842D1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59122486A (ja) * 1982-12-28 1984-07-14 Eisai Co Ltd ２−メチルクロモン誘導体およびその製造方法
US4503052A (en) * 1983-05-16 1985-03-05 Eli Lilly And Company 7-(2-(Substituted cinnolinoyl)amino)acetamido)-1-oxa-beta-lactams

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1022544A (en) * 1972-12-21 1977-12-13 Yukiyasu Murakami Process of preparing a heterocyclic acyl group-substituted cephalosporin derivative
US4098799A (en) * 1973-04-18 1978-07-04 Warner-Lambert Company 3-formylchromones
US3904618A (en) * 1973-12-26 1975-09-09 Lilly Co Eli 7-substituted cephalosporin compounds
EP0003115A1 (fr) * 1978-01-16 1979-07-25 Sandoz Ag Dérivés de pénicilline, per se et utilisables comme antibiotique antibacterien et leur préparation
US4159268A (en) * 1978-03-24 1979-06-26 American Cyanamid Company 3-Chromonecarboxamido derivatives of penicillins
CH645905A5 (de) * 1979-04-09 1984-10-31 Eisai Co Ltd Cephalosporinderivate, verfahren fuer ihre herstellung und antibakteriell wirkende zusammensetzungen, die solche verbindungen enthalten.
JPS565487A (en) * 1979-06-26 1981-01-20 Eisai Co Ltd Cephalosporin compound, its preparation, and antimicrobial comprising it

Also Published As

Publication number Publication date
EP0049309A1 (fr) 1982-04-14
EP0049308A1 (fr) 1982-04-14
DE3070842D1 (de) 1985-08-08
DE3067794D1 (en) 1984-06-14
JPS5764698A (en) 1982-04-19
EP0049309B1 (fr) 1984-05-09
US4309354A (en) 1982-01-05
US4352801A (en) 1982-10-05

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